2015-11-10 07:41:29

Prelude

Prelude

Today's Topics

  • Disorder and disease
    • Affective disorders
    • Schizophrenia
    • Parkinson's
    • Huntington's

Framework

  • Symptoms
  • Genetic risk
  • Neurological factors
  • Neurochemical factors

The face of depression

The face of depression

Major affective (emotional) disorders

  • Types
    • Anxiety
    • Depression
    • Bipolar disorder

Major affective (emotional) disorders

  • Heritability
    • proportion of variance in trait accounted for by genetic factors
    • Monozygotic: .69
    • Dizygotic: .13

Depression

  • Symptoms
    • Insomnia, lethargy, loss of pleasure, interest, energy
  • Agitation
  • Lasting for several weeks or more
  • Prevalence (~16% lifetime)
  • Females 2-3x males

Cognitive model

…negative cognitive biases in depression are facilitated by increased influence from subcortical emotion processing regions combined with attenuated top-down cognitive control.

(Disner et al. 2011)

(Disner et al. 2011)

(Disner et al. 2011)

(Disner et al. 2011)

Neurological factors

(Videbech and Ravnkilde 2004)

(Videbech and Ravnkilde 2004)

Neurological factors

(Fitzgerald et al. 2008)

  1. patients v. controls, (b) patients on SSRIs, (c) patients v. ctrls (happy stim), (d) patients v. controls (sad stim)

Neurological Factors

  • Persistent activation in amygdala
  • Amygdala and dorsolateral prefrontal cortex (DLPFC) inversely related
  • (Siegle et al. 2002)

(Siegle et al. 2002)

(Siegle et al. 2002)

Disturbed sleep

  • Less slow wave (stage 3 and 4)
  • More REM earlier in night (typical is longer REM as night goes on)

Pharmacological factors

  • Lowered thyroid function
  • High/chronic cortisol levels
  • Monoamine hypothesis, (Schildkraut 1965)
    • More: euphoria
    • Less: depression
    • Resperine (antagonist for NE & 5-HT) can cause depression

Pharmacological factors

  • Serotonin hypothesis, (Coppen 1967).

(Samuelsson et al. 2006)

Revisiting the serotonin hypothesis

Treatments for depression

"First generation" drugs

  • Monoamine oxidase (MAO) inhibitors
    • MAO destroys excess monoamines in terminal buttons
    • MAO-I’s boost monoamine levels
    • side effects may include "serotonin syndrome"

"First generation" drugs

  • Tricyclics
    • Inhibit NE, 5-HT reuptake
    • Upregulate monoamine levels
    • but non-selective = side effects, esp. blood pressure/heart rate

"Second and third generation" drugs

  • Selective Serotonin Reuptake Inhibitors (SSRIs)
    • Block action of 5-HT transporter (SERT)
    • Fluoxetine (Prozac, Paxil, Zoloft)
    • Prolong duration 5-HT in synaptic cleft
    • Also increase brain steroid production

Others

  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
    • e.g., Cymbalta, Effexor
  • Norepinephrine reuptake inhibitors (NRI, NERI) or adrenergic reuptake inhibitors (ARI)
  • Norepinephrine-Dopamine Reuptake Inhbitors (NDRIs)
    • e.g., Wellbutrin

Problems with monoamine/5-HT hypothesis

  • Too simplistic
  • NE, 5-HT interact
  • Drugs fast acting (min), but improvement slow (weeks)

What do drugs do, then?

  • Receptor sensitivity altered?
    • Presynaptic serotonin autoreceptors compensate
    • Postsynaptic upregulation of NE/5-HT effects
    • Link to neurotrophin BDNF, (Duman and Monteggia 2006)
    • BDNF boosts neurogenesis

Exercise as a treatment

Drugs vs. therapy

(DeRubeis, Siegle, and Hollon 2008)

(DeRubeis, Siegle, and Hollon 2008)

(DeRubeis, Siegle, and Hollon 2008)

Depression's widespread impact

  • Widespread brain dysfunction
  • Prefrontal cortex, amygdala, HPA axis, circadian rhythms
  • Genetic + environmental factors
  • Disturbance in 5-HT, NE systems, cortisol

Bipolar disorder

The face of bipolar disorder

Bipolar disorder

  • Formerly “manic depression” or “manic depressive disorder
  • Alternating mood states
    • Mania or hypomania (milder form)
    • Depression
  • Cycles 3-6 mos in length, but
    • Rapid cycling (weeks or days)
  • Suicide risk 20-60x normal population, (Baldessarini, Pompili, and Tondo 2006)

Symptoms

Prevalence, subtypes

  • 1-3% prevalence
  • Subtypes
    • Bipolar I: manic episodes, possible depressive ones
    • Bipolar II: no manic episodes but hypomania + depression

Genetics

  • Overlap between bipolar disorder and schizophrenia
  • Genes for voltage-gated Ca++ channels
    • Regulate NT, hormone release
    • Gene expression, cell metabolism
  • (Craddock and Sklar 2013)

Brain responses to emotional faces ≠ depression

(Lawrence et al. 2004)

(Lawrence et al. 2004)

Amyg, Hip volume reduced,

(Hallahan et al. 2011)

Drug treatments

  • Mood stabilizers
    • Lithium (Li)
    • Valproate
  • Anticonvulsants
    • GABA agonists
    • Usually to treat epilepsy
    • e.g. lamotrigine (Lamictal)
  • Antipsychotics

Effects of Lithium

  • Reduces mania, minimal effects on depressive states
  • Increases/preserves PFC, hip, amyg volume
  • downregulates DA, glu; upregulates GABA
  • modulates 5-HT, NE
  • (Malhi et al. 2013)

What does lithium do?

At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission…

(Malhi et al. 2013)

An Unquiet Mind

BP summed-up

  • Changes in mood, but ≠ depression
  • Genetic + environmental risk
  • Changes in emotion processing network activity, size of hippocampus
  • But, heterogeneous
  • No simple link to a specific NT system

Interlude

Love and Mercy

Interlude

Interlude

Schizophrenia

The face of schizophrenia

Overview

  • Lifetime prevalence ~ 1/100
  • 1/3 chronic & severe
  • Onset post-puberty, early adulthood
  • Pervasive disturbance in mood, thinking, movement, action, memory, perception

Screening (Yale PRIME test)

  1. I think that I have felt that there are odd or unusual things going on that I can’t explain.
  2. I think that I might be able to predict the future.
  3. I may have felt that there could possibly be something interrupting or controlling my thoughts, feelings, or actions.

http://www.schizophrenia.com/sztest/primetest.pdf

Screening (continued)

  1. I get confused at times whether something I experience or perceive may be real or may be just part of my imagination or dreams.
  2. I have thought that it might be possible that other people can read my mind, or that I can read other’s minds.
  3. I wonder if people may be planning to hurt me or even may be about to hurt me.

Historical background

  • Bleuler
    • Introduced “schizophrenia” or “split mind”
    • Not multiple personality disorder
  • Kraeplin
    • Dementia Praecox and Paraphrenia (1919)
    • Emphasized developmental and hereditary origins

"Positive" symptoms

  • “Additions” to behavior
  • Disordered thought
  • Delusions of grandeur, persecution
  • Hallucinations (usually auditory)
  • Bizarre behavior

"Negative" symptoms

  • “Reductions” in behavior
  • Poverty of speech
  • Flat affect
  • Social withdrawal
  • Impaired executive function
  • Anhedonia (loss of pleasure)
  • Catatonia (reduced movement)

Biological bases

  • Genetic disposition
  • Brain abnormalities
  • Developmental origins

Genetic disposition

Ventricles larger, esp in males

Hip and amyg smaller

  • Related to ventricular enlargement?
  • Early disturbance in brain development?

Rapid gray matter loss in adolescents?

Dopamine hypothesis

Evidence for DA hypothesis

  • DA (D2 receptor) antagonists (e.g. chlorpromazine)
    • improve positive symptoms
  • DA agonists
    • amphetamine, cocaine, L-DOPA
    • mimic or exacerbate symptoms

Evidence against…

  • New drugs
    • (e.g. Clozapine) INCREASE DA in frontal cortex, effect 5-HT
  • Mixed evidence for high DA metabolite levels in CSF
  • Glutamate hypothesis
    • Underactivation of NMDA receptors?
    • NMDA receptor role in learning, plasticity

Schizophrenia summed up

  • Wide-ranging disturbance of mood, thought, action, perception
  • Broad changes in brain structure, function, chemistry
  • Genetic risk + environmental factors

Neurodegenerative disorders

  • Parkinson's
  • Huntington's
  • Alzheimer's

Parkinson's

Maurice White, Musician

The Faces of Parkinson's

Parkinson's

  • Slow, absent movement, resting tremor
  • Cognitive deficits, depression
  • DA Neurons in substantia nigra degenerate
  • Treatments

Huntington's

The face of Huntington's

Huntington's

  • Formerly Huntington’s Chorea
    • "Chorea" from Greek for "dance"
    • “Dance-like” pattern of involuntary movements
  • Cognitive decline
  • Genetic + environmental influences
  • Disturbance in striatum
  • No effective treatment

Next time…

  • Exams due at midnight on Monday, 11/16.
  • Audition

Postlude

References

Babyak, Michael, James A Blumenthal, Steve Herman, Parinda Khatri, Murali Doraiswamy, Kathleen Moore, W Edward Craighead, Teri T Baldewicz, and K Ranga Krishnan. 2000. “Exercise Treatment for Major Depression: Maintenance of Therapeutic Benefit at 10 Months.” Psychosomatic Medicine 62 (5). LWW: 633–38. http://journals.lww.com/psychosomaticmedicine/Abstract/2000/09000/Exercise_Treatment_for_Major_Depression_.6.aspx.

Baldessarini, Ross J., Maurizio Pompili, and Leonardo Tondo. 2006. “Suicide in Bipolar Disorder: Risks and Management.” CNS Spectrums 11 (06): 465–71. doi:10.1017/S1092852900014681.

Coppen, Alec. 1967. “The Biochemistry of Affective Disorders.” The British Journal of Psychiatry 113 (504): 1237–64. doi:10.1192/bjp.113.504.1237.

Craddock, Nick, and Pamela Sklar. 2013. “Genetics of Bipolar Disorder.” The Lancet 381 (9878): 1654–62. doi:10.1016/S0140-6736(13)60855-7.

DeRubeis, Robert J., Greg J. Siegle, and Steven D. Hollon. 2008. “Cognitive Therapy Versus Medication for Depression: Treatment Outcomes and Neural Mechanisms.” Nature Reviews Neuroscience 9 (10): 788–96. doi:10.1038/nrn2345.

Disner, Seth G., Christopher G. Beevers, Emily A. P. Haigh, and Aaron T. Beck. 2011. “Neural Mechanisms of the Cognitive Model of Depression.” Nature Reviews Neuroscience 12 (8): 467–77. doi:10.1038/nrn3027.

Duman, Ronald S., and Lisa M. Monteggia. 2006. “A Neurotrophic Model for Stress-Related Mood Disorders.” Biological Psychiatry 59 (12): 1116–27. doi:10.1016/j.biopsych.2006.02.013.

Fitzgerald, Paul B., Angela R. Laird, Jerome Maller, and Zafiris J. Daskalakis. 2008. “A Meta-Analytic Study of Changes in Brain Activation in Depression.” Human Brain Mapping 29 (6): 683–95. doi:10.1002/hbm.20426.

Hallahan, Brian, John Newell, Jair C. Soares, Paolo Brambilla, Stephen M. Strakowski, David E. Fleck, Tuula Kieseppä, et al. 2011. “Structural Magnetic Resonance Imaging in Bipolar Disorder: An International Collaborative Mega-Analysis of Individual Adult Patient Data.” Biological Psychiatry, Bipolar Disorder: Genes and Brain Development, 69 (4): 326–35. doi:10.1016/j.biopsych.2010.08.029.

Lawrence, Natalia S, Andrew M Williams, Simon Surguladze, Vincent Giampietro, Michael J Brammer, Christopher Andrew, Sophia Frangou, Christine Ecker, and Mary L Phillips. 2004. “Subcortical and Ventral Prefrontal Cortical Neural Responses to Facial Expressions Distinguish Patients with Bipolar Disorder and Major Depression.” Biological Psychiatry 55 (6): 578–87. doi:10.1016/j.biopsych.2003.11.017.

Malhi, Gin S., Michelle Tanious, Pritha Das, Carissa M. Coulston, and Michael Berk. 2013. “Potential Mechanisms of Action of Lithium in Bipolar Disorder.” CNS Drugs 27 (2): 135–53. doi:10.1007/s40263-013-0039-0.

Samuelsson, M., J. Jokinen, A.-L. Nordström, and P. Nordström. 2006. “CSF 5-HIAA, Suicide Intent and Hopelessness in the Prediction of Early Suicide in Male High-Risk Suicide Attempters.” Acta Psychiatrica Scandinavica 113 (1): 44–47. doi:10.1111/j.1600-0447.2005.00639.x.

Schildkraut, Jj. 1965. “The Catecholamine Hypothesis of Affective-Disorders - a Review of Supporting Evidence.” American Journal of Psychiatry 122 (5): 509–22.

Siegle, Greg J., Stuart R. Steinhauer, Michael E. Thase, V. Andrew Stenger, and Cameron S. Carter. 2002. “Can’t Shake That Feeling: Event-Related fMRI Assessment of Sustained Amygdala Activity in Response to Emotional Information in Depressed Individuals.” Biological Psychiatry 51 (9): 693–707. doi:10.1016/S0006-3223(02)01314-8.

Thompson, Paul M., Christine Vidal, Jay N. Giedd, Peter Gochman, Jonathan Blumenthal, Robert Nicolson, Arthur W. Toga, and Judith L. Rapoport. 2001. “Mapping Adolescent Brain Change Reveals Dynamic Wave of Accelerated Gray Matter Loss in Very Early-Onset Schizophrenia.” Proceedings of the National Academy of Sciences 98 (20): 11650–55. doi:10.1073/pnas.201243998.

Videbech, Poul, and Barbara Ravnkilde. 2004. “Hippocampal Volume and Depression: A Meta-Analysis of MRI Studies.” American Journal of Psychiatry 161 (11). Am Psychiatric Assoc: 1957–66. doi:10.1176/appi.ajp.161.11.1957.